The overall objective of this Program Project Grant is to improve the outcome of patients with hematologic malignancies by developing curative strategies using radiolabeled monoclonal antibodies (RAb) in the setting of hematopoietic cell transplantation (HCT). Our prior studies have established the feasibility, safety and anti-tumor efficacy of this approach. We now propose to improve, refine and extend this treatment for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS) and lymphomas by targeting radionuclides to neoplastic cells using monoclonal antibodies (Ab) directed at the CD45 antigen present on the surface of these malignancies. We will pursue this global objective in three highly interactive, complementary projects. In Project 1 (Leukemia), we will conduct a Phase II study of 131l-labeled anti-CD45 antibody (BC8) in conjunction with fludarabine (FLU), 2 Gy total body irradiation (TBI) and allogeneic HCT in patients with AML in remission (Aim 1), extend the approach to patients lacking histocompatibility locus antigen (HLA)-matched donors by investigating 131l-BCS in the setting of haplo-identical transplantation for AML, ALL and MDS (Aim 2) and explore the use of 90Yttrium-BC8, FLU, and 2 Gy TBI in a Phase I dose-finding study conducted at our center and at the City of Hope Medical Center for AML, ALL and MDS (Aim 3). In Project 2 (Lymphoma), we will define the optimal BCS protein dose for targeting CD45 in patients with B and T cell lymphomas (Aim 1), compare and contrast targeting of lymphoma cells with radiolabeled anti-CD20 and anti-CD45 RAb (Aim 2), compare the relative merits of 111ln-BC8 and 86Y-BC8 for conducting trace-labeled biodistribution studies and dosimetry (Aim 3), and estimate the maximally tolerated dose of 90Y-labeled BCS Ab that can be administered safely to lymphoma patients in a Phase I dose-escalation trial (Aim 4). In Project 3 (Pretargeting Trials), we plan to conduct the first in human clinical trials of multi-step pretargeted radioimmunotherapy directed at the CD45 antigen in patients with leukemia (Aim 1) and lymphoma (Aim 2). In addition, we will compare the biodistributions of radioactivity in tumor sites and in normal organs following targeting with directly radiolabeled 111ln-BC8 antibody or with pretargeted BC8-streptavidin followed by 111In-DOTA-biotin. We predict that these comparative biodistribution studies will confirm our hypothesis that pretargeted radioimmunotherapy (PRIT) will deliver much more radioactivity to tumor cells and much less radioactivity to normal tissues than is possible with conventional radioimmunotherapy (RIT). We anticipate that the investigations described in this application will allow us to maximize the therapeutic efficacy and minimize the toxicity of myeloablative RIT for hematologic malignancies.